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Design of (N)-methanocarba adenosine 5'-uronamides as species-independent A3 receptor-selective agonists. Bioorg Med Chem Lett 2008 May 01;18(9):2813-9

Date

04/22/2008

Pubmed ID

18424135

Pubmed Central ID

PMC2430186

DOI

10.1016/j.bmcl.2008.04.001

Scopus ID

2-s2.0-42949156868   37 Citations

Abstract

2-Chloro-5'-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A(3) adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A(1)AR. Therefore, we varied substituents at the N(6) and C2 positions in search of compounds that have improved A(3)AR selectivity and are species independent. An N(6)-methyl analogue was balanced in affinity at mouse A(1)/A(3)ARs, with high selectivity in comparison to the A(2A)AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A(3)AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A(3)AR selectivity more effectively than similar chains attached at the 3-position of the N(6)-benzyl group.

Author List

Melman A, Gao ZG, Kumar D, Wan TC, Gizewski E, Auchampach JA, Jacobson KA

Author

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine
Adenosine A3 Receptor Agonists
Alkanes
Animals
Binding Sites
Drug Design
Humans
Hydrophobic and Hydrophilic Interactions
Mice
Models, Chemical
Nucleosides
Ribose
Structure-Activity Relationship
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0